A variety of microfluidic devices of disparate, design have been developed in the past often with the goal of reducing sample volume requirements in bioanalytical methods, integrating multiple steps into automated processes, integrating sample preparation and analysis, and connecting to the full volume world of samples and procedures.
In the absence of standards controlling external dimensional form factors, the nature of the upstream and downstream external interface, and the length, cross-sectional geometry, and diameter of the internal microfluidic pathways, such microfluidic devices often proved incompatible with one another and with existing upstream purification and downstream analytical devices.
Despite advances in microfabrication, making possible analysis at microliter, even nanoliter or picoliter, scale, many biological and environmental samples are first acquired in volumes far greater than, the scale of existing microfluidic analytical devices.
Modular microfluidic technology can combine moving samples on microchips. While a focus in microfluidics has been integration of multiple functions onto a single device, the objects have been achieved through an alternative approach that allows modular integration of functions across multiple devices. This modular concept is based on technologies, that allow arrays of capillaries to be connected simply by plugging two connectors together (U.S. Pat. No. 6,551,839; U.S. patent application Ser. No. 11/229,065; U.S. Pat. Nos. 6,190,616; 6,423,536; U.S. patent application Ser. No. 09/770,412; U.S. Pat. No. 6,870,185; U.S. patent application Ser. Nos. 10/125,045; 10/540,658; 10/750,533; 11/138,018; all of which are herein incorporated by reference in their entirety). In addition to creating connectors, the interface between the arrays also creates true zero dead-volume valves and routers. The present disclosure provides guidance on how to connect and disconnect microchips containing fluidic circuits to other microchips or arrays of capillaries, develops new microchip designs incorporating two, three, or more microchips, provides new functionality, including fraction collection, new applications, and instrumentation design. This new technology is termed modular nanofluidics and the use of microchips in modular nanofluidics is referred to as “modular microfluidic microchips” or “modular microchips.”
Modular microfluidic microchips have many applications in the life sciences and medicine. Modular microchips create devices can perform single functions or logically clustered groups of functions. More complex processes are created by docking two microdevices and transferring the processed samples. For example, one microdevice might perform PCR amplification and cleanup of a series of target DNAs, a second might perform cycle sequencing reactions, and may connect to a third device that performs DNA sequence analysis. Similarly, for proteomics, one device might perform a first dimension of a separation and a second device a second orthogonal separation. The ability to connect devices in a “plug-and-play” manner permits processes with different rates, cycle times, or throughputs to proceed independently. Sets of modular microchips can be prepared and incubated in hotels. When one step in a sample preparation process is complete, modular microchips for the next step can be docked, loaded, and, if necessary, moved to hotels for incubation of the next step. When sample preparation is complete, the modular microchips can interface with a high throughput CAE microchip, mass spectrometer, flow cytometer, or other analysis devices.
The modular approach lets macroscale devices such as automation and robotics work with nanoscale sample preparation and analysis. The positional accuracy necessary for modular manipulation is well within the existing capability of current robotic systems and much less than required in the microelectronics industry. Stages and stepper motors are now capable of less than 1 μm positioning and greater than 5 μm positioning is fairly routine. Modular microchips can leverage the extensive automation capabilities directly to accelerate development and deployment of nanoscale devices.
The modular microfluidic approach can combine microchip-based technologies with automation systems to create a technology platform to completely automate nanoscale sample preparation methods and link it to many types of analysis. In this instant invention, examples of how to apply the invention to develop DNA sequence sample preparation and analysis, AFLP analysis, PCR analysis, MLVA analysis, cycle sequencing, DNA fragment analysis for genotyping, and fragment analysis for DNA sequencing.
In this invention, guidance is provided on how microscale and nanoscale devices can be connected and how to perform sample preparation and analysis on microchips. We also teach how to connect different microchips that perform specialized functions comprising microchip valves, reactors, movement of fluids, mixing, performance of different biochemistries, and analysis methods.